tbuckley/cabot-search huggingface dataset:
CYP4F2-Catalyzed Metabolism of Arachidonic Acid Promotes Stromal Cell-Mediated Immunosuppression in Non–Small Cell Lung Cancer
Authors: Xuehan Chen, Yanzhuo Liu, Yang Wang, Chenlong Wang, Xuewei Chen, Yu Xiong, Lilong Liu, Xi Yuan, Honglin Tang, Chong Shu, Jing Zhang, Austin M. Guo, Honglei Chen, Jing Yang
Journal: Cancer Research (2022)

The identification of a role for CYP4F2-dependent metabolism in driving immune evasion in non-small cell lung cancer reveals a strategy to improve the efficacy of immunotherapy by inhibiting CYP4F2. See related article by Van Ginderachter, p. 3882.
The next frontier in ADME science: Predicting transporter-based drug disposition, tissue concentrations and drug-drug interactions in humans
Authors: Flavia Storelli, Mengyue Yin, Aditya R. Kumar, Mayur K. Ladumor, Raymond Evers, Paresh P. Chothe, Osatohanmwen J. Enogieru, Xiaomin Liang, Yurong Lai, Jashvant D. Unadkat
Journal: Pharmacology & Therapeutics (2022)
Unique and common <scp>TCR</scp> repertoire features of Ni<sup>2+</sup>‐, Co<sup>2+</sup>‐, and Pd<sup>2+</sup>‐specific human <scp>CD154</scp> + <scp>CD4</scp>+ T cells
Authors: Franziska Riedel, Marina Aparicio‐Soto, Caterina Curato, Lucas Münch, Amro Abbas, Hermann‐Josef Thierse, Wiebke K. Peitsch, Andreas Luch, Katherina Siewert
Journal: Allergy (2022)

Abstract Background Apart from Ni 2+ , Co 2+ , and Pd 2+ ions commonly trigger T cell‐mediated allergic contact dermatitis. However, in vitro frequencies of metal‐specific T cells and the mechanisms of antigen recognition remain unclear. Methods Here, we utilized a CD154 upregulation assay to quantify Ni 2+ ‐, Co 2+ ‐, and Pd 2+ ‐specific CD4+ T cells in peripheral blood mononuclear cells (PBMC). Involved αβ T cell receptor (TCR) repertoires were analyzed by high‐throughput sequencing. Results Peripheral blood mononuclear cells incubation with NiSO 4 , CoCl 2 , and PdCl 2 increased frequencies of CD154 + CD4+ memory T cells that peaked at ~400 μM. Activation was TCR‐mediated as shown by the metal‐specific restimulation of T cell clones. Most abundant were Pd 2+ ‐specific T cells (mean 3.5%, n = 19), followed by Co 2+ ‐ and Ni 2+ ‐specific cells (0.6%, n = 18 and 0.3%, n = 20) in both allergic and non‐allergic individuals. A strong overrepresentation of the gene segment TRAV9‐2 was unique for Ni 2+ ‐specific TCR (28% of TCR) while Co 2+ and Pd 2+ ‐specific TCR favorably expressed TRAV2 (8%) and the TRBV4 gene segment family (21%), respectively. As a second, independent mechanism of metal ion recognition, all analyzed metal‐specific TCR showed a common overrepresentation of a histidine in the complementarity determining region 3 (CDR3; 15% of α‐chains, 34% of β‐chains). The positions of the CDR3 histidine among metal‐specific TCR mirrored those in random repertoires and were conserved among cross‐reactive clonotypes. Conclusions Induced CD154 expression allows a fast and comprehensive detection of Ni 2+ ‐, Co 2+ ‐, and Pd 2+ ‐specific CD4+ T cells. Distinct TCR repertoire features underlie the frequent activation and cross‐reactivity of human metal‐specific T cells.
Endoscopic ultrasound-guided portal pressure gradient measurement
Authors: Edson Guzmán-Calderón, Belén Martínez-Moreno, José Ramón Aparicio
Journal: Endoscopy (2022)

A 55-year-old man with a past medical history of chronic liver disease and small esophageal varices on upper gastrointestinal endoscopy underwent endoscopic ultrasound-guided portal pressure gradient (EUS-PPG) measurement.
Notch Signaling Promotes Mature T-Cell Lymphomagenesis
Authors: Xin Gao, Chenguang Wang, Suhaib Abdelrahman, Nermin Kady, Carlos Murga-Zamalloa, Peter Gann, Maria Sverdlov, Ashley Wolfe, Avery Polk, Noah Brown, Nathanael G. Bailey, Kedar Inamdar, Sandro Casavilca-Zambrano, Jaime Montes, Carlos Barrionuevo, Luis Taxa, John Reneau, Christian W. Siebel, Ivan Maillard, Ryan A. Wilcox
Journal: Cancer Research (2022)

Peripheral T-cell lymphomas (PTCL) are agressive lymphomas that develop from mature T cells. The most common PTCLs are genetically, molecularly, and clinically diverse and are generally associated with dismal outcomes. While Notch signaling plays a critically important role in both the development of immature T cells and their malignant transformation, its role in PTCL is poorly understood, despite the increasingly appreciated function of Notch in regulating the proliferation and differentiation of mature T cells. Here, we demonstrate that Notch receptors and their Delta-like family ligands (DLL1/DLL4) play a pathogenic role in PTCL. Notch1 activation was observed in common PTCL subtypes, including PTCL-not otherwise specified (NOS). In a large cohort of PTCL-NOS biopsies, Notch1 activation was significantly associated with surrogate markers of proliferation. Complementary genetically engineered mouse models and spontaneous PTCL models were used to functionally examine the role of Notch signaling, and Notch1/Notch2 blockade and pan-Notch blockade using dominant-negative MAML significantly impaired the proliferation of malignant T cells and PTCL progression in these models. Treatment with DLL1/DLL4 blocking antibodies established that Notch signaling is ligand-dependent. Together, these findings reveal a role for ligand-dependent Notch signaling in driving peripheral T-cell lymphomagenesis.This work demonstrates that ligand-dependent Notch activation promotes the growth and proliferation of mature T-cell lymphomas, providing new therapeutic strategies for this group of aggressive lymphomas.
Trends in the Use of Promotional Language (Hype) in Abstracts of Successful National Institutes of Health Grant Applications, 1985-2020
Authors: Neil Millar, Bojan Batalo, Brian Budgell
Journal: JAMA Network Open (2022)

The integrity of the grant application process is important to the success of the entire research enterprise. However, little information is available concerning the prevalence and evolution of subjective or promotional language ("hype") that has the potential to undermine objectivity in the writing and evaluation of grant applications.To assess changes over time in the use of hype in abstracts of National Institutes of Health (NIH) grant applications.This cross-sectional study assessed the prevalence of promotional adjectives in abstracts in the NIH archive from 1985 to 2020.From all abstracts in the NIH RePORTER (Research Portfolio Online Reporting Tools: Expenditures and Results) archive, adjectives were automatically extracted, and their frequencies in the most recent year (2020) were assessed relative to the start year (1985). Adjectives that shifted significantly in frequency and that carried a promotional sense (ie, hype) were retained, and patterns of change were assessed by plotting yearly frequencies (1985-2020). By grouping the adjectives based on shared semantic properties, broad meanings commonly expressed by hype were identified. Absolute change was measured as the difference in normalized frequency between 1985 and 2020. Relative change was measured as the percentage change in normalized frequency in 2020 relative to 1985, or the first year of occurrence.In total, 901 717 abstracts were analyzed and 139 adjective forms were identified as hype. Among these 139 adjective forms, 130 hype adjectives increased in frequency by 7690 words per million (wpm) (mean [SD] relative increase, 1378% [3132%]), while 9 hype adjectives decreased in frequency by 686 wpm (mean [SD] relative decrease, 44% [18%]). The largest absolute increases were for the terms novel (1054 wpm), critical (555 wpm), and key (461 wpm), while the largest relative increases were for the terms sustainable (25 157%), actionable (16 114%), and scalable (13 029%). Hype most often serves to promote the significance, novelty, scale, and rigor of a project; the utility of the expected outcomes; the qualities of the investigators and research environment; and the gravity of the problem; as well as conveying the personal attitudes of the applicants.Levels of hype in successful NIH grant applications have increased over time from 1985 to 2020. The findings in this study should serve to sensitize applicants, reviewers, and funding agencies to the increasing prevalence of subjective, promotional language in funding applications.
Use of First-Line Immune Checkpoint Inhibitors and Association With Overall Survival Among Patients With Metastatic Melanoma in the Anti–PD-1 Era
Authors: Nayan Lamba, Patrick A. Ott, J. Bryan Iorgulescu
Journal: JAMA Network Open (2022)

In 2015, first-line programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICI) were Food and Drug Administration (FDA)-approved and National Comprehensive Cancer Network (NCCN)-recommended for patients with stage IV melanoma. Few studies have assessed the overall survival (OS) and usage rate associated with first-line ICI following 2015.To determine the rates of ICI use for metastatic melanoma following FDA approval in 2015 and characterize OS associated with first-line ICI use in this patient population.In this retrospective, nationwide cohort study, adult patients (≥20 years of age) with newly diagnosed stage IV cutaneous melanoma from 2010 to 2019 were identified using the US National Cancer Database (NCDB). Data were released by NCDB in March 2022 and analyzed in June 2022.Patients were compared based on first-line ICI receipt vs not.The OS and use of first-line ICI in 2016 to 2019 were assessed using multivariable Cox and logistic regression, respectively. To account for immortal time bias in receiving ICI, landmark time points were used (the 50th and 75th percentile times from diagnosis to ICI initiation).Among 16 831 patients with stage IV melanoma, 11 435 (67.9%) of patients were male; 116 (0.69%) were Asian or Pacific Islander, 475 (2.82%) were Hispanic, 270 (1.60%) were non-Hispanic Black, 15 711 (93.55%) were non-Hispanic White, and 145 (0.86%) were other race and ethnicity; the median (IQR) age at diagnosis was 64 (54-73) years. First-line immunotherapy use increased from 8.9% (127 of 1429) in 2010 to 38.8% (685 of 1766) in 2015, and 62.5% (1223 of 1958) in 2019. Median OS improved from 7.7 months (95% CI, 7.1-8.6 months) in 2010 to 17.5 months (95% CI, 14.9-19.8 months) in 2018. For patients diagnosed in 2016 or later, OS improved with first-line ICI (median OS using the 78-day landmark: 43.7 months [95% CI, 38.1-49.1 months] vs 16.1 months [95% CI, 13.5-19.3 months] for targeted therapy or chemotherapy; adjusted P < .001)-even after adjusting for patient, disease, and treatment factors. Results were similar for the 48-day landmark. This included patients presenting with brain metastases (first-line ICI median OS using the 78-day landmark: 19.9 months [95% CI, 17.2-25.0 months] vs 10.7 months for targeted therapy [95% CI, 9.5-12.3 months], adjusted P = .001). First-line ICI use varied by patients' age, insurance status, zip code-level household income, and treating hospital type.Following anti-PD-1 approval in 2015, first-line ICI was associated with substantial OS improvements for patients with stage IV melanoma, including those with brain metastases. As of 2019, 38% of patients still were not receiving first-line ICI in the US, with use varying by patients' socioeconomic factors.
Analysis of Quality-of-Life Outcomes by Drug Class in Cancer Clinical Trials
Authors: Bellinda L. King-Kallimanis, Upal Basu-Roy, Sandra Nolte
Journal: JAMA Oncology (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Plasma Cell-Free DNA Predicts Survival and Maps Specific Sources of Injury in Pulmonary Arterial Hypertension
Authors: Samuel B. Brusca, Jason M. Elinoff, Yvette Zou, Moon Kyoo Jang, Hyesik Kong, Cumhur Y. Demirkale, Junfeng Sun, Fayaz Seifuddin, Mehdi Pirooznia, Hannah A. Valantine, Carl Tanba, Abhishek Chaturvedi, Grace M. Graninger, Bonnie Harper, Li-Yuan Chen, Justine Cole, Manreet Kanwar, Raymond L. Benza, Ioana R. Preston, Sean Agbor-Enoh, Michael A. Solomon
Journal: Circulation (2022)

Cell-free DNA (cfDNA) is a noninvasive marker of cellular injury. Its significance in pulmonary arterial hypertension (PAH) is unknown.Plasma cfDNA was measured in 2 PAH cohorts (A, n=48; B, n=161) and controls (n=48). Data were collected for REVEAL 2.0 (Registry to Evaluate Early and Long-Term PAH Disease Management) scores and outcome determinations. Patients were divided into the following REVEAL risk groups: low (≤6), medium (7-8), and high (≥9). Total cfDNA concentrations were compared among controls and PAH risk groups by 1-way analysis of variance. Log-rank tests compared survival between cfDNA tertiles and REVEAL risk groups. Areas under the receiver operating characteristic curve were estimated from logistic regression models. A sample subset from cohort B (n=96) and controls (n=16) underwent bisulfite sequencing followed by a deconvolution algorithm to map cell-specific cfDNA methylation patterns, with concentrations compared using t tests.In cohort A, median (interquartile range) age was 62 years (47-71), with 75% female, and median (interquartile range) REVEAL 2.0 was 6 (4-9). In cohort B, median (interquartile range) age was 59 years (49-71), with 69% female, and median (interquartile range) REVEAL 2.0 was 7 (6-9). In both cohorts, cfDNA concentrations differed among patients with PAH of varying REVEAL risk and controls (analysis of variance P≤0.002) and were greater in the high-risk compared with the low-risk category (P≤0.002). In cohort B, death or lung transplant occurred in 14 of 54, 23 of 53, and 35 of 54 patients in the lowest, middle, and highest cfDNA tertiles, respectively. cfDNA levels stratified as tertiles (log-rank: P=0.0001) and REVEAL risk groups (log-rank: P<0.0001) each predicted transplant-free survival. The addition of cfDNA to REVEAL improved discrimination (area under the receiver operating characteristic curve, 0.72-0.78; P=0.02). Compared with controls, methylation analysis in patients with PAH revealed increased cfDNA originating from erythrocyte progenitors, neutrophils, monocytes, adipocytes, natural killer cells, vascular endothelium, and cardiac myocytes (Bonferroni adjusted P<0.05). cfDNA concentrations derived from erythrocyte progenitor cells, cardiac myocytes, and vascular endothelium were greater in patients with PAH with high-risk versus low-risk REVEAL scores (P≤0.02).Circulating cfDNA is elevated in patients with PAH, correlates with disease severity, and predicts worse survival. Results from cfDNA methylation analyses in patients with PAH are consistent with prevailing paradigms of disease pathogenesis.
Laboratory-Confirmed COVID-19–Associated Hospitalizations Among Adults During SARS-CoV-2 Omicron BA.2 Variant Predominance — COVID-19–Associated Hospitalization Surveillance Network, 14 States, June 20, 2021–May 31, 2022
Authors: Fiona P. Havers, Kadam Patel, Michael Whitaker, Jennifer Milucky, Arthur Reingold, Isaac Armistead, James Meek, Evan J. Anderson, Andy Weigel, Libby Reeg, Scott Seys, Susan L. Ropp, Nancy Spina, Christina B. Felsen, Nancy E. Moran, Melissa Sutton, H. Keipp Talbot, Andrea George, Christopher A. Taylor, Pam Daily Kirley, Nisha B. Alden, Kimberly Yousey-Hindes, Kyle P. Openo, Chloe Brown, Cody T. Schardin, Kelly Plymesser, Grant Barney, Kevin Popham, Laurie M. Billing, Nasreen Abdullah, Tiffanie M. Markus, Mary Hill
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

Beginning the week of March 20–26, 2022, the Omicron BA.2 variant of SARS-CoV-2, the virus that causes COVID-19, became the predominant circulating variant in the United States, accounting for >50% of sequenced isolates.* Data from the COVID-19–Associated Hospitalization Surveillance Network (COVID-NET) were analyzed to describe recent COVID-19–associated hospitalization rates among adults aged ≥18 years during the period coinciding with BA.2 predominance (BA.2 period [Omicron BA.2 and BA.2.12.1; March 20–May 31, 2022]). Weekly hospitalization rates (hospitalizations per 100,000 population) among adults aged ≥65 years increased threefold, from 6.9 (week ending April 2, 2022) to 27.6 (week ending May 28, 2022); hospitalization rates in adults aged 18–49 and 50–64 years both increased 1.7-fold during the same time interval. Hospitalization rates among unvaccinated adults were 3.4 times as high as those among vaccinated adults. Among hospitalized nonpregnant patients in this same period, 39.1% had received a primary vaccination series and 1 booster or additional dose; 5.0% had received a primary series and ≥2 boosters or additional doses. All adults should stay up to date† with COVID-19 vaccination, and multiple nonpharmaceutical and medical prevention measures should be used to protect those at high risk for severe COVID-19 illness, irrespective of vaccination status§ (1).
Trial of a Phosphodiesterase 4 Inhibitor for Idiopathic Pulmonary Fibrosis
Authors: Luca Richeldi, Susanne Stowasser, Toby M Maher
Journal: New England Journal of Medicine (2022)

FibrosisTo the Editor: Richeldi et al. (June 9 issue) 1 reported prompt stabilization in lung function in patients with idiopathic pulmonary fibrosis (IPF) who received a preferential phosphodiesterase 4B (PDE4B) inhibitor and a rapid decline in the forced vital capacity (FVC) in patients who received placebo.Over a period of 12 weeks, the mean decline in the FVC was 77.7 ml among patients in the placebo group with background antifibrotic use and 83.8 ml among all patients in the placebo group (Figs. 2 and 3 in their article, and Fig. S5 in the Supplementary Appendix, available with the full text of their article at NEJM.org).These findings should not be dismissed lightly.A rapid decline in the FVC in patients with IPF is a rare event in clinical practice; the rate of natural decline in FVC is approximately 150 ml over a period of 1 year. 2 The authors postulate the reason for the discrepancy to be that patients enrolled in this trial had more progressive disease than the patients in other trials.However, the demographic and clinical characteristics of the enrolled patients at baseline are similar to those of patients in other IPF trials.The biologic plausibility of the implied therapeutic effect of the PDE4B inhibitor -by stabilizing, or perhaps even reversing, the fibrosis as early as 2 weeks after the initiation of treatment in patients with IPF -is very low.The results of this trial therefore must be interpreted with caution and raise important questions that temper optimism.
Risk of Macrovascular and Microvascular Disease in Diabetes Diagnosed Using Oral Glucose Tolerance Test With and Without Confirmation by Hemoglobin A1c: The Whitehall II Cohort Study
Authors: Adam G. Tabák, Eric J. Brunner, Joni V. Lindbohm, Archana Singh-Manoux, Martin J. Shipley, Naveed Sattar, Mika Kivimäki
Journal: Circulation (2022)

It is unclear whether replacing oral glucose tolerance test (OGTT) with hemoglobin A1c (HbA1c) measurement for diagnosing diabetes is justified. We aimed to assess the proportion of OGTT-diagnosed diabetes cases that can be confirmed by HbA1c and to examine whether individuals with OGTT diagnosis but nondiagnostic HbA1c are at higher risk of macrovascular and microvascular disease.Participants were 5773 men and women from the population-based Whitehall II prospective cohort study in the United Kingdom. New OGTT diabetes cases diagnosed in clinical examinations in 2002 to 2004 and 2007 to 2009 were assessed for HbA1c confirmation (≥6.5%) in these and subsequent clinical examinations in 2012 to 2013 and 2015 to 2016. All participants were followed up for major cardiovascular events through linkage to electronic health records until 2017 and for incident chronic kidney disease (estimated glomerular filtration rate <60 mL·min-1·1.73 m-2) until the last clinical examination. In analysis of vascular disease risk, new OGTT-diagnosed diabetes cases with and without diagnostic HbA1c and preexisting diabetes cases were compared with diabetes-free participants.Of the 378 (59.3%) participants with OGTT-diagnosed diabetes, 224 were confirmed by HbA1c during 4.1 years (SD, 4.1 years) of follow-up. We recorded 942 cardiovascular events over 12.1 years. After adjustment for nonmodifiable risk factors and compared with the 4997 diabetes-free participants, 371 participants with new HbA1c-confirmed diabetes and 405 participants with preexisting diabetes had increased risk of cardiovascular disease (hazard ratio, 1.53 [95% CI, 1.12-2.10] and 1.85 [95% CI, 1.50-2.28], respectively). The corresponding hazard ratios in the analysis of incident chronic kidney disease (487 cases; follow-up, 6.6 years) were 1.69 (95% CI, 1.09-2.62) for 282 participants with new HbA1c-confirmed diabetes and 1.67 (95% CI, 1.22-2.28) for 276 participants with preexisting diabetes. In both analyses, OGTT cases with nondiagnostic HbA1c (n=149 and 107) had a risk (hazard ratio, 0.99-1.07) similar to that of the diabetes-free population.More than 40% of OGTT-diagnosed diabetes cases were not confirmed by HbA1c during an extended follow-up. However, because these individuals have a risk of cardiovascular disease and chronic kidney disease similar to that of the diabetes-free population, replacement of OGTT with HbA1c-based diagnosis appears justified.